NKG2D ligands mediate immunosurveillance of senescent cells

Sagiv, Adi; Burton, Dominick G. A.; Moshayev, Zhana; Vadai, Ezra; Wensveen, Felix M.; Ben‐Dor, Shifra; Golani, Ofra; Polić, Bojan; Krizhanovsky, Valery

doi:10.18632/aging.100897

Cited by 234 publications

(196 citation statements)

References 59 publications

(106 reference statements)

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“…The SASP, composed of pro‐inflammatory cytokines, chemokines, growth factors, and proteases, can modulate the senescent cell's microenvironment and promote its interaction with the immune system (Coppe et al , ; Lujambio et al , ; Sagiv & Krizhanovsky, ; Sagiv et al , ). We found that compared to 2‐day cultures, our trophoblast cultures on day 5 indeed exhibited significantly upregulated gene sets associated with the immune response, cytokine activity, and major signaling pathways regulating the SASP, including JAK‐STAT and MAPK (Fig D).…”

Section: Resultsmentioning

confidence: 99%

Molecular pathways of senescence regulate placental structure and function

et al. 2019

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The placenta is an autonomous organ that maintains fetal growth and development. Its multinucleated syncytiotrophoblast layer, providing fetal nourishment during gestation, exhibits characteristics of cellular senescence. We show that in human placentas from pregnancies with intrauterine growth restriction, these characteristics are decreased. To elucidate the functions of pathways regulating senescence in syncytiotrophoblast, we used dynamic contrast‐enhanced MRI in mice with attenuated senescence programs. This approach revealed an altered dynamics in placentas of p53−/−, Cdkn2a−/−, and Cdkn2a−/−;p53−/− mice, accompanied by histopathological changes in placental labyrinths. Human primary syncytiotrophoblast upregulated senescence markers and molecular pathways associated with cell‐cycle inhibition and senescence‐associated secretory phenotype. The pathways and components of the secretory phenotype were compromised in mouse placentas with attenuated senescence and in human placentas from pregnancies with intrauterine growth restriction. We propose that molecular mediators of senescence regulate placental structure and function, through both cell‐autonomous and non‐autonomous mechanisms.

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Section: Resultsmentioning

confidence: 99%

Molecular pathways of senescence regulate placental structure and function

et al. 2019

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“…It is thought the clearance of senescent cells can result from the activity of both adaptive and innate immunity; the latter resulting from the increased expression of ligands (e.g. NKG2D) on senescent cells that target them for selective killing by natural killer (NK) lymphocytes (Sagiv et al, 2016). Therefore, mechanisms to augment cellular immunity or NK function might be therapeutically beneficial in some settings.…”

Section: Translating Senescencementioning

confidence: 99%

Senescence in Health and Disease

Sharpless

2017

Cell

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Many cellular stresses activate senescence, a persistent hyporeplicative state characterized in part by expression of the p16INK4a cell cycle inhibitor. Senescent cell production occurs throughout life and plays beneficial roles in a variety of physiological and pathological processes including embryogenesis, wound healing, host immunity and tumor suppression. Meanwhile, the steady accumulation of senescent cells with age also has adverse consequences. These non-proliferating cells occupy key cellular niches and elaborate pro-inflammatory cytokines, contributing to aging-related diseases and morbidity. This model suggests that the abundance of senescent cells in vivo predicts ‘molecular’, as opposed to chronologic, age, and that senescent cell clearance may mitigate aging-associated pathology.

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“…Drug‐induced transcription of MICA and PVR genes involves the transcriptional factor E2F and is dependent on the cellular redox state . Notably, NKG2D and DNAM‐1 ligands have been shown to be expressed by senescent cells and drug‐induced senescent tumor cells, unmasking an important role of NK cells for the immune surveillance of senescent cells …”

Section: Introductionmentioning

confidence: 99%

Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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NK cells are lymphocytes of the innate immune system, which are able to deal promptly with stressed cells. Cellular senescence is a cell stress response leading to cell cycle arrest that plays a key role during tissue homeostasis and carcinogenesis. In this review, how senescent cells trigger an immune response and, in particular, the ability of NK cells to recognize and clear senescent cells are discussed. Special attention is given to the NK cell‐mediated clearance of senescent tumor cells. NK cells kill senescent cells through a mechanism involving perforin‐ and granzyme‐containing granule exocytosis, and produce IFN‐γ following senescent cell interaction, leading to hypothesize that NK cell‐mediated immune clearance of senescent cells not only relies on direct killing but also on cytokine production, that in turn can promote macrophage activation. These aspects, as well as the ability of the senescence‐associated secretory phenotype and senescent cell‐produced extracellular vesicles to modulate NK cell effector functions, are described.

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NKG2D ligands mediate immunosurveillance of senescent cells

Cited by 234 publications

References 59 publications

Molecular pathways of senescence regulate placental structure and function

Molecular pathways of senescence regulate placental structure and function

Senescence in Health and Disease

Senescent cells: Living or dying is a matter of NK cells

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